Cancer is associated with increased proliferation and/or decreased apoptosis. Both of these processes are regulated by a complex interplay of transcription, protein synthesis, protein-protein interactions, protein phosphorylation and protein degradation. More than 80% of cellular proteins are degraded by the ubiquitin/proteasome system (UPS) (Adams, 2004a). Deregulation of various components of the UPS resulting in increased degradation of cell cycle inhibitors or pro-apoptotic proteins (e.g. p21Cip1, p27Kip1, p53, Bax, IκBα) or decreased degradation of cell cycle stimulators or anti-apoptotic proteins (e.g. cyclins, Bcl-2) can contribute to the transformed phenotype (Adams, 2004a; Mani and Gelmann, 2005; and Nalepa et al., 2006). The UPS has two distinct steps: recognition/ubiquitination and degradation (reviewed in Ciechanover, 1994; Hochstrasser, 1995). The ubiquitin-protein ligase system was discovered in 1983 and involves three enzymes and results in the transfer of multiple ubiquitin molecules, polypeptides of 76 amino acids, to the target protein (Hershko et al., 1983). Polyubiquitin-flagged proteins are then recognized by the proteasome, a large multi-subunit complex found in the cytoplasm and nuclei of all eukaryotic cells, which was first described in 1988 (Arrigo et al., 1988). Degradation of proteins is mediated by the 20S catalytic complex (Coux et al., 1996; Voges et al., 1999), containing three proteolytic enzymes, namely peptidylglutamyl peptide hydrolyzing (PGPH), trypsin-like (T-L), and chymotrypsin-like (CT-L) activities, residing in the β1, β2, and β5 catalytic subunits, respectively (Mani and Gelmann, 2005; Adams, 2004b).
In contrast to normal cells, which just require a low level of survival signals to stay alive (Raff, 1992), cancer cells typically have acquired a series of mutations that render them dependent on strong activation of one or a few survival pathways (Downward, 2003). One of these is the degradation of cellular proteins by the UPS, which drive cell cycle progression and/or survival. Therefore, the UPS has become a promising target for anti-cancer strategies (reviewed in Adams, 2004b; Mani and Gelmann, 2005; Nalepa et al., 2006; Burger and Seth, 2004).
One proteasome inhibitor that has been studied extensively is the dipeptide boronic acid analog PS-341 (bortezomib, VELCADE) (for reviews, see Adams, 2004a; Richardson et al., 2005). Preclinical studies have shown that VELCADE induces apoptosis in cancer cell lines derived from multiple myeloma (MM) (Hideshima et al., 2001), lung (Ling et al., 2003; Mortenson et al., 2004) and prostate cancer (Williams et al., 2003; Ikezoe et al., 2004). Likewise, in xenografts implanted in nude mice, VELCADE inhibits the growth of human prostate cancer (Williams et al., 2003; Adams et al., 1999), squamous cell carcinoma (Sunwoo et al., 2001), and ovarian cancer (Bazzaro et al., 2006). However, in other tumors such as human A549 lung tumors (Mortenson et al., 2004) or MIA-PaCa2 pancreatic tumors (Bold et al., 2001), even when administered in combination with other agents, VELCADE has only marginal effects. Currently, VELCADE has been approved by the Food and Drug Administration (FDA) for treatment of relapsed/refractory MM (Richardson et al., 2003; Adams and Kauffman, 2004), as a single agent or in combination with conventional therapies (Jagannath et al., 2005; Oakervee et al., 2005), and is being investigated for solid tumors (Aghajanian et al., 2002), including non-small cell lung cancer (Davies et al., 2004), renal cell cancer (Davies et al., (2004), Kondagunta et al., (2004)) and prostate cancer (reviewed in Scagliotti, 2006; Papandreou and Logothetis, 2004).
However, VELCADE is associated with undesired side effects in MM patients (Bang et al., 2006) and does not display substantial antitumor activity in other cancers (Scagliotti, 2006; Papandreou and Logothetis, 2004).
Thus, there remains a need in the art for proteasome inhibitors having better antitumor activity profile and less toxicity.